L-desoxyephedrine inhalant preparation



L-DESOXYEPHEDRINE INHALANT PREPARATION Donalee L. Tahern, Lak e Blntf, 111., ass'ignor to Abbott Laboratories, North Chicago, 111., a corporation of Illinois No Drawing. Application December 31, 1953, Serial No. 401,731

4 claims. (Ci. 167-54) This invention relates to new inhalant preparations, that is, those preparations suitable for intra-nasal administration and sinus irrigation. I

The treatment of pathologic disorders of the upper respiratory system is a well developed medical practice and the treatment of such disorders as the common cold and allergies by the use of inhalants is already well established. In spite of the fact that large number of preparations have been tried, and some have met with considerable commercial success, there is still a wide recognition that the ideal inhalant has not been found. Among the more important characteristics of an ideal inhalant are blandness or freedom from irritation. Secondly, the inhalant should provide prompt vasoconstr'ictive action which will persist over a suitable period of time up to several hours by one application. Thirdly, the inhalant should be compatible with numerous therapeutic agents such as the antibiotics, the sulfa drugs, antihistaminics and antiseptics. Also it should be capable of dilution so that a single preparation might be suitable for use as nose drops and also, upon dilution, as a spray.

The vasoconst-n'ctor' in an inhalant, which is deemed quite necessary by all authorities, should be one which is non-irritating, is free from secondary rebound phenomena, should cause little or no respiratory acceleration, should have a low order of stimulation on the central nervous system and should have low vasopressor efiect.

The most commonly known yasocorist'iictor's are ephedrine and compounds bearing a close similarity to this compound chemical structure. Amphetamine has been used as a vascconstrictor but-itisnot well accepted because of its pronounced stimulation of the central nervous system. Likewise l-ephedrine is characterized by a certain amount of central nervous stimulation and secondary rebound. In summary it may be said that prior to this invention no one of the presently known vasoco'nstrictors is sufficiently bland while at the same; time giving high initial vasoconstrictive action and satisfactory duration.

It is an object of this invention therefore to provide an inhalant preparationwhich has all of the desirable properties of an ideal inhalant;

According to the practice of the invention there is now provided an inhalant preparation which gives high initial vasoconstrict ive action plus reasonably long action and at the same time issubstantially free from any of the nude sirable side efiects which are normally associated with this class of drugs. Essentially thisinhalant consists of l-desoxyephedrine in a pharmaceutical carrier adapted for application to the nasal mucosa. The inhalant of this invention contains l-desoxye'phedrine substantially free from the d-form. l=DesoXyephedIine is not a new chemical and is prepared by the resolutionof dldesoXyephedrine by known methods. Because of its freedom from irritation and lack of side effects, preparations containing l -desox yep'hedrine are especially useful for treatment of children, cafdiac artway penetrates and the like.

ited States Patent These persensaave previous been deprived of ice the beneficial effects of a vasoconstrictive inhalant, for the most part.

d-Desoxyephedrine is well known for its high activity as a central nervous stimulant, and it is used in certain preparations for the control of obesity by depressing the appetite and for elevating mood in depressive states by providing a temporary feeling of well being in the patient. it was very surprising therefore to find that l-desoxyephedrine exhibits such excellent properties as a topical vasoconstrictor, combined with practically a total lackof undesirable side effects. This activity would certainly not be suggested by a comparison with the activity of ddesoxyephedrine which is not particularly suitable for use in nose drops because of its high central nervous sysitern stimulation, its high vasopressorresponse and its respiratory acceleration. The same is true for d-l desoxyephedrine although to a somewhat lesser degree. Viewed in another way, one would not find l-desoxyephedrine to be at all satisfactory for use as a central nervous system stimulant when substituted for d-desoxyephedrine. I

By the same token one would not be led to expect such favorable activity or" l-desoxyephedrine from a knowledge of the activity and side effects of l-ephedrine, the most commonly known vasoconstrictor. l-Ephedrine exhibits moderate to high vasopressor effect, a fairly high degree of central nervous system stimulation, high respiratory acceleration and causes a substantial amount of rebound. With this knowledge of l-ephedrine in mind one would certainly not be inclined to predict the good vasoconstrictive response of l-desoxyephedrine, in combinatio with its almost total lack of side effects.

in clinical examinations conducted up to the present time, l-desoxyephedrine has been found to be the most bland of all vasoconstrictors and patients have actually commented on the pleasantness of inhalant preparations employing l-desoxyep'hedrine. on clinical trial the ldesoxyephedrine preparations have evidenced prompt shrinkage of the nasal mucous membrane and from two to four hours of continual contraction from a single application of the inhalant preparation. l-Desoxyephedrine does not produce any secondary rebound phenomena, in contrast to results reported and observed in the case of some nasal va'soconstrictors now commercially available. There is little or no central nervous stimulation, little or no respiratory acceleration and little or no vasopressor respouse from the application of l-desoxyephedrine to the nasal passages. For these reasons children and cardiac patients may use l-desoxyephedrine without danger or discomfort.

As pointed out above this unusual activity of ldesoxyephedrine could not have been suggested nor predicted by one who has knowledge" of the activity of closely related chemical compounds. The optical isomer of l desoxyephedrine is noted for efiects which are opposite the effects that have now distinguished l-desoxyephdrir'iei as an ideal preparation in the inhalant field. While the racemic form of desoxyephedrine has been used to a certain extent in nasal preparations the results certainly are not suggestive of the freedom from undesirable side efiects of l-des'oiiyephedrine as a vasoconstrictor. Again by comparison with l ephedrine, l-desoxyephedrine has a freedom from side effects which could not be predicted by one familiar with the activity of l-ephedrine;

The l-desoxyep'hedrine is available in the form of the basic compound and it is also readily available in the form of its inorganic salts such as the chloride and the sulfate, as well as the organic salts. A particularly suitable salt of l-desoxyephedrine is obtained in the resolution of the (ll-form with tartaric acid; Thus messy ephedrine tart-rate isobtained in" a form which canrea'd'ily be made'pure enough for normal usei'n' prenarations. Concentration of 0.25% of l-desoxyephedrine give good response and amounts up to 4.0% or more can be used.

7, The vehicle, or-excipient in which the l-desoxyephedrim: or salt thereof is actually compounded in the making of a suitable inhalant preparation may be varied widely Within the skill of those familiar with this art. For example the following are representative of suitable pharmaceutical carriers for l-desoxyephedrine base or salts thereof in inhalant preparations: aqueous solutions, oil solutions, jellies, viscous aqueous or oily preparations in which the viscosity has been increased by the addition of a thickening agent, oil in water emulsion type preparations, mucilaginous preparations deriving their isotonicity from dextrose, salt solutions and the like, vapor ,inhalan'tsin which the active ingredient is suspended on or absorbed by an inertm-aterial such as cotton, paper or the like. The l-desoxyephedrine may be used in any of the aforementioned forms either primarily by itself or. in combination with aromatics such as methol, camphor and eucalyptol or additionally in combination with antibiotics, antihistamines, sulfa drugs and antiseptics, many of which will be shown in detail in the examples. Any, none or all of these additives may be employed if desired and in most instances their activity will be enhanced due to the vasoconstrictive action of the l-desoxyephedrine.

The following examples are presented in order to describe the details of the invention more clearly. It should be understood however that the invention is not intended to be limited in any way by the examples.

Example I V An aqueous preparation especially adapted for application to the nasal mucosa is made up according to the following directions:

l-Desoxyephedrine tartrate "gm-.. 5.0 Benzethonium chloride .gm 0.2 Sodium chloride 2m 8.0 Distilled water, q. s cc 1000.0

The l-desoxyep'hedrine tartrate is dissolved in water along with the sodium chloride. The benzethonium chloride preservative is added and sufiicient water is added to bring the volume up to 950 cc. The pH is adjusted to about 6 with normal sodium hydroxide (requiring about 15-20 cc.). The volume is brought up to 1000 cc. and the material is sterilized through a Selas filter.

. Example II A preparation especially adapted for application to the nasal mucosa is prepared according to the following directions:

l-Desoxyephedrine tartrate gm 2.5 Benzethonium chloride .gm 0.2 Sodium chloride gm 8.5 Distilled Water, q.-s cc 1000.0

This preparation is made up in the same way previously described in Example I.

Example III A combination type is prepared according to the following directions:

Distilled water, q. s cc 1000l in deriving its isotonicity from dextrose.

The gramicidin is dissolved in propylene glycol and the l-desoxyephedrine tartrate is dissolved in about 800 cc. of water. The pH is adjusted to about 6.0 with N/ 1 sodium hydroxide solution. The neomycin and methapyrilene are added and dissolved by stirring. Then the wetting agent is added along with the remaining sodium chloride. The propylene glycol solution of gramicidin is added dropwise with vigorous stirring to the aqueous solution and the saccharin and eucalyptol are likewise added. The solution is brought up to full volume with additional distilled water and the total solution is filtered through a Selas filter.

Example IV A nose drop or spray preparation is made up according to the folowing directions:

Mix the chlorobutanol and menthol, add alcohol and glycerin, add dextrose and water and adjust to pH about 6. Example V A nose drop or nasal spray preparation is made up in concentrated form according to the following directions:

l-Desoxyephedrine tartrate gm 3.5 Sodium chloride gm 22.0 Methyl p-hydroxybenzoate gm 0.52 Sodium bicarbonate gm 17.0 Glycerin gm 22.0 Distilled water, q. s cc. 1000.0

This preparation is compounded in a manner similar to Examples I to 111 and must be diluted with 4 parts of distilled water before use.

Example VI A nose drop or nasal spray preparation is made up according to the following directions:

Q. s. distilled water.

This preparation is compounded in the manner set forth in previous examples and differs from other preparations Adjust to pH about 6.

Example VII A nose drop or nasal spray preparation is made up according to the following directions: 7

l-Desoxyephedrine tartrate "gm..- 0.5 Potassium sulfate pm 05 Sodium phosphate dibasicu; ...gm 0.5 Potassium chloride 7 gm 0.15 Sodium chlori e 7 7 m 0.15 Dextrose anhydrous ..gm 0.9969 Distilled water, q. s.. cc '100 Example VIII 3 An inhalant preparation in which the viscosity has .been increased is made up according to the following directions: 7

Percent w./v.

l-Desoxyephedrine tartrate 1.0 Chlorobutanol 0.5 Sodium chloride 0.85 Pectin 1.5

Q. -s. distilled water.

In this formula the pectin increases the viscosity of the solution and causes retention within the, nasal passages for a longer period of time. It is also possible to use aromatics such as menthol, camphor and eucalyptol in this formula. Likewise it has been found that 3.5% polyvinyl alcohol or 2 /2%-3% methyl cellulose can be substituted for the pectin.

Example IX l-Desoxyephedrine is well suited for use in a tube-type inhaler, the l-desoxyephedrine being volatile. A suitable preparation is made up according to the following directions:

gm. l-Desoxyephedrine 0.30 -Menthol 0.03 Light oil 0.10

The l-desoxyephedrine and menthol are dissolved or suspended in the oil and the oil is poured over a porous object such as a wad of cotton or roll of porous paper. The cartridge is then placed in a standard inhaler-type tube. Example X An oil-type preparation suitable for use as nose drops or as a nasal spray is made up according to the following directions:

l-Desoxyephedrine gm /2 Menthol gm /2 Q. s. with liquid parafiin fluid oz /2 The l-desoxyephedrine and menthol are dissolved in the light liquid parafiin and a small amount of preservative may be added if desired. The menthol can be eliminated in this formula if one desires only the vascoconstrictive action of the l-desoxyephedrine.

Example XI Another oil-type preparation which is especially suitable for its blandness is made up according to the following directions:

l-Desoxyephedrine gm 2.5 Menthol om 10 Camphor gm l Methyl salicylate cc.. Eucalyptol cc 2 Light liquid petroleum, q. s cc 1000.0

Mix the menthol, camphor, eucalyptol and methyl salicylate and add about 75 cc. of the petroleum until solution is effected. Then add suflicient of the light liquid petroleum with l-desoxyephedrine dissolved therein to make 1000 cc. Filter if necessary.

Example XII An emulsion-type product suitable for nose drops or nasal spray is made up according to the following directions:

I-Desoxyephedrine tartrate gm 1.0 Menthol gm 0.10 Camphor gm 0.10 Chlorobutanol gm 0.50 Sodium benzoate gm 0.50 Eucalyptol cc..- 0.25 Acacia, powdered gm 12.5 Heavy liquid petrolatum cc 50 Distilled water, q. s cc 100 l-Desoxyephedrine ExampleXlIl Amucilaginous spray preparation is made up according to the following directions:

Percent w./v. l-Desoxyephedrine tartrate 1.0 Gum tragacanth 0.5 Q. s. distilled water.

Example XIV A jelly preparation adapted for application to the nasal mucosa is prepared according to the following directions:

Grams l-Desoxyephedrine 1.0 Menthol 0.2 White soft parafiin 100.0

The l-desoxyephedrine and the menthol are incorporated into the white soft paraflin with stirring, and with heating it necessary. The paraffin is selected for a desired degree of fluidity at normal body temperature.

Example XV Another jelly-like product is prepared without the use of any oil according to the following directions:

l-Desoxyephedrine tartrate 'gm 0.3 Tragacanth mucilage (3%) cc 10 Water cc 10 The l-desoxyephedrine tartrate is dissolved in water and the tragacauth mucilage is added with stirring until a thick homogeneous jelly-like preparation is obtained.

Example XVI An oily-type preparation which does not have the disadvantage of possibly causing lipoid pneumonitis is prepared according to the following directions:

gm 1.0 Ethyl olcate gm 99.0

The ethyl oleate is distinguished from parafn'n type oils in that it is absorbable by lung tissue and if any is inhaled into the lungs it will be absorbed. To this formula may also be added any of the other commonly used ingredients such as aromatics and preservatives.

Example XVII A combination type preparation adapted for application to the nasal mucosa is prepared according to the following directions:

Percent w./v. l-Desoxyephedrine tartrate 0.25

Methapyrilene hydrochloride 0.1 Q. s. distilled water.

The methapyrilene in this preparation is an elfective antihistaminic agent which aids in quick return of the nasal mucosa to normal condition.

Example XVIII A composition for application to the nasal mucosa is prepared according to the following directions:

l-Desoxyephedrine tartrate percent w./v 1.0 Nitromersol 1:5000

Q. s. with water.

The preparation is made isotonic with a suitable amount of sodium chloride. The nitromersol in this instance is an efiectlve antiseptic. If desired bland mineral oil may 7 acid.

be substituted for water in the foregoing preparation, in

which case an equivalent amount of l-desoxyephedrine Sulfathiazole sesquihydrate 2.5 Sodium sulfite anhydrous 2.0 Q. s. distilled water.

Example XX Another combination type inhalant is prepared according to the following directions:

' Percent w./v. l-Desoxyephe'drine tartrate 0.25 Sodium sulfacetimide 2.5 Sodium thiosulfate 0.1

Q. s. distilled water.

The pH of this preparation is adjusted to about 6.8 with dilute sodium hydroxide solution or dilute hydrochloric If desired a preservative such as methyl p hydroxybenzoate may be added. 7

It will be seen from the foregoing discussion of the invention and the numerous examples presented herein that l-desoxyephedrine has properties as a vasoconstrictor which make it ideally suited for use in nose drop or other inhalant preparation. The high activity of l-desoxyephedrine coupled with its almost total lack of undesirable side efiects could not be predicted by one skilled in the art and easily distinguishes preparations employing this.

chemical from those, heretofore known in the art. As

will be seen from the examples the mode in which the l-desoxyephedrine tartrate is put up for use in thetreatment of nasal mucosa is not critical. It is necessary only that it be combined with a suitable pharmaceutical carrier which will enable the active chemical to be brought in contact with the nasal mucosa. Due to the blandness of l-desoxyephedrine it is not necessary to use local anesthetics or any other type of emollient.

Also due to its blandness it is ideally suited for a pediatric nose drop preparation.

l-Desoxyephedrine 'is unusually free from any bad amine odor and it does not'oxidize nor develop a bad odor on ageing; This feature further distinguishes it that all such practice of the invention shall be covered hereunder provided it falls within the scope of the invention as defined in the appended claims;

I claim: a

l. A composition in dosage formadapted for use as an inhalant for local application comprising at least about 0.25 of a member of the group consisting of l-desoxyephedrine and salts thereof, and a significant amount of a pharmaceutical carrier adapted for application to the nasal mucosa, said composition being substantially free of d-desoxyephedrine.

2. A composition in aqueous dosage unit form adapted for use as an inhalent for local application comprising at least about 0.25% of a member of the group consisting of l-desoxyephedrine and salts thereof and a significant amount of an aqueous pharmaceutical carrier, said composition being substantially free of d-desoxyephedrine.

3. A composition in oily dosage unit form adapted for use as an inhalant for local application comprising at least about 0.25 of a member of the group consisting of l-desoxyephedrine and salts thereof and a significant amount of an oily pharmaceutical carrier, said composition being substantially free of d-desoxyephedrine.

4. An inhaler having as the active agent therein a composition comprising l-desoxyephedrine absorbed on a porous solid material References Cited in the file of this patent 'Extra Pharmacopoeia, vol. 1, 23rd ed. (1952), page 

1. A COMPOSITION IN DOSAGE FORM ADAPTEED FOR USE AS AN INHALANT FOR LOCAL APPLICATION COMPRISING AT LEAST ABOUT 0.25% OF A MEMBER OF THE GROUP CONSISTING OF 1-DESOXYEPHEDRIN AND SALTS THEREOF, AND A SIGNIFICANT AMOUNT OF A PHARMACEUTICAL CARRIER ADAPTED FOR APPLICATION TO THE NASAL MUCOSA, SAID COMPOSITION BEING SUBSTANTIALLY FREE OF D-DESOXYEPHEDRINE. 